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Inhibition of miR-135a-5p attenuates vascular smooth muscle cell proliferation and vascular remodeling in hypertensive rats

Abstract

Proliferation of vascular smooth muscle cells (VSMCs) greatly contributes to vascular remodeling in hypertension. This study is to determine the roles and mechanisms of miR-135a-5p intervention in attenuating VSMC proliferation and vascular remodeling in spontaneously hypertensive rats (SHRs). MiR-135a-5p level was raised, while fibronectin type III domain-containing 5 (FNDC5) mRNA and protein expressions were reduced in VSMCs of SHRs compared with those of Wistar–Kyoto rats (WKYs). Enhanced VSMC proliferation in SHRs was inhibited by miR-135a-5p knockdown or miR-135a-5p inhibitor, but exacerbated by miR-135a-5p mimic. VSMCs of SHRs showed reduced myofilaments, increased or even damaged mitochondria, increased and dilated endoplasmic reticulum, which were attenuated by miR-135a-5p inhibitor. Dual-luciferase reporter assay shows that FNDC5 was a target gene of miR-135a-5p. Knockdown or inhibition of miR-135a-5p prevented the FNDC5 downregulation in VSMCs of SHRs, while miR-135a-5p mimic inhibited FNDC5 expressions in VSMCs of both WKYs and SHRs. FNDC5 knockdown had no significant effects on VSMC proliferation of WKYs, but aggravated VSMC proliferation of SHRs. Exogenous FNDC5 or FNDC5 overexpression attenuated VSMC proliferation of SHRs, and prevented miR-135a-5p mimic-induced enhancement of VSMC proliferation of SHR. MiR-135a-5p knockdown in SHRs attenuated hypertension, normalized FNDC5 expressions and inhibited vascular smooth muscle proliferation, and alleviated vascular remodeling. These results indicate that miR-135a-5p promotes while FNDC5 inhibits VSMC proliferation in SHRs. Silencing of miR-135a-5p attenuates VSMC proliferation and vascular remodeling in SHRs via disinhibition of FNDC5 transcription. Either inhibition of miR-135a-5p or upregulation of FNDC5 may be a therapeutically strategy in attenuating vascular remodeling and hypertension.

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Fig. 1: Effects of miR-135a-5p on VSMC proliferation in WKYs and SHRs.
Fig. 2: Ultrastructural alterations induced by the miR-135a-5p inhibitor in the VSMCs of WKYs and SHRs.
Fig. 3: MiR-135a-5p and FNDC5 expression in the VSMCs of WKYs and SHRs.
Fig. 4: Effects of miR-135a-5p on FNDC5 expression in the VSMCs of WKYs and SHRs.
Fig. 5: Effects of FNDC5 knockdown on the VSMC proliferation in WKYs and SHRs.
Fig. 6: Effects of FNDC5 on VSMC proliferation.
Fig. 7: Effects of FNDC5 overexpression on the VSMC proliferation in SHRs.
Fig. 8: Effects of miR-135a-5p knockdown in WKYs and SHRs on blood pressure and miR-135a-5p and FNDC5 expression.
Fig. 9: Effects of miR-135a-5p knockdown in WKYs and SHRs on PCNA expression and vascular remodeling.

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Acknowledgements

This study was supported by the National Natural Science Foundation of China [32071106, 91639105, 31871148, and 81770426].

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Authors

Contributions

CY, YT, QC, YHL, YMK, and GQZ designed experiments. CY, YT, NW, GWW, FZ, JZL, HZ, and ADC conducted the experiments. CY, YT, NW, GWW, JYC, JJW, and GQZ performed data and statistical analyses. CY, YT, and GQZ wrote the manuscript, with contributions from all the other authors. GQZ supervised the study. All authors approved the final version for submission.

Corresponding author

Correspondence to Guo-qing Zhu.

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The authors declare no competing interests.

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Ye, C., Tong, Y., Wu, N. et al. Inhibition of miR-135a-5p attenuates vascular smooth muscle cell proliferation and vascular remodeling in hypertensive rats. Acta Pharmacol Sin (2021). https://doi.org/10.1038/s41401-020-00608-x

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Keywords

  • microRNA
  • FNDC5
  • hypertension
  • vascular smooth muscle cells
  • proliferation
  • vascular remodeling

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